Phosphoramidates



United States This invention is directed to'phosphoramidates having the formula Gin NH-R In this a'nd su'eeeedin'g formulae, R' representsa lower alkyl' radical containing frorn' l to4' carbon atoms, inelusive, R is selected from the group consisting of hyd-rogeh and a'lower 'al-kyl radiealcontaining from l'to 4 carbon atoms," inclusive, and ii is an-integer offrom 1 to 5, inclusive. Theinve'ntion also relates to methods and compositions for controlling parasites attacking warm:

. blooded animals,

Domestieanimals -are subjeet to attack by'a number of diiferent' parasites; including fleas, flies; 1ice,- ticks, screw-worms and cattle -grub's' as well as the heln'iinthie 2 esophageal region or the abdominal viscera while. the bomb fly larvae migrate through the spinal" canal. Dil'ringtheir life in the host, the larvae feedupon host'tissue.- After from about three to six months,-dependirig.-upoh the climatic conditions, the larvae locate in the skin and particularly the skin on the back ofthe host. Here, the larva opens a-hole through the skin, usually in the choicest part of the hide, and grows rapidly. forabout six Weeks. The larva thereafter leaves the animal through the-hole in the skin,.falls to the groundand shortly thereafter, depending upon the prevailingtemperature, pupates for its-transformation to the adult stage. Theorganisms cause considerable damage to the carcass'of beef-animals. In infestedareas, losses frombeef trimmings and prime leather run as high asten dollars a'carcass. Thus-the yearly loss to'-the cattle'industries of the United-States runs-into the millions of dollars.

Another undesirable parasite is the screw-worm fly (Cdllz'trogaamericana). It can breedonly in the tissues of living warm-hooded animals and it mustdepend upon finding a wounded or diseased part'of the hosts body in which its young can begindevelopment. This parasite is particularly prevalent in Southern and Southwestern States and in-Central and South American countries. In the areas-where it normally-occurs,.it is one of the greatest enemies ofall the inseetspecies :with' which E the livestock owner must-eontend.- Underthe" present system of livestock production, man-made wounds occasioned by marking, branding, shearingQcastrating, dehorning, and docking afford ample and fertile breeding grounds for screwworms, as do injuries resulting from such plants parasites such'as lungworm, stomach W'o'rrr'rs and'gastro' V intestinalworms; Thehelminthic" parasites-"include the strongyloidsgcooperid'sand asearids and are the causative agents'of ascariasis, trichostrongylosis and gross parasitism The 'hehninths grow and'mature invariousorgans but particularly the gastro-intestinal tract of their host; In the usual life cycle, the ova pass out of the body with the'fecal droppings, hatch and reach theirother parts of the" body such-as th'e-"liven orth'e mags; as

Withlungworms. The parasites during maturationand growth have a very deleterious effect upon the animahand its rate of growth. In the intestine'the parasites erode the epithelial tissues-bringing about'hemorrhage; anemia, weakness" and tissue necrosis; Animals, if they ddnot succumb to gross parasitism are rendered economically unfit by weakness} lowere'cl vitality, and poor growth and reproduction; It is est-ii'nated' thafi the losses aecruin'g to the cattle industry of the' Unit'ed'states from gross parasitism amount to about fiftymillio'n dollarspery'ear, with yearly losses due solely to mortality running-as high as nine million dollars.

One of the undesirable parasites-in animals is'tlie' cat tle'grub. This grub is-the' larval form of'the heelifly (Hypoderma lineatum), the bomb fiy (Hypodermzz bot i5) or the bot fly (Dermatobia hbmiriis). The latter fly is found mostly inth'e- Central-andSouth American countries? The heel and bomb/flies appear inthe United 7 States from February through August and f-astendheir eggs near the base of the hair on their host. The bot fly is not seasonal in theC'entral and South American habitat and lays its eggs on an insect such as a mosquito or common fly which carries the eggs to the warm-blooded host. Following their attachment, the eggs of the various flies hatch in four or five days and the larvae bore through theskin of the host. The heel fly larvae migrate to the as cacti and needlegrass, from fighting ,.fron1 diseased tissues,. and= from the attacks of blood-sucking in ects.

Newboinam'mals are particularly susceptible to intesta tionof th'e navel cord. The flygenerally seeks the edges oradryportionfot wound on whichto' deposit" eg s: The eggs fasten tightly to the tissue surface in compaetshinglelike massesz' "The' eggs hatch in about 11 hours and the-'youh'g wli'itisli worir'is immediately burrow into theflesh, wheretliey'feed and grow fora period offrom'4 to *Tdays. Theworms'aftr attaining full rowth in'th'e wound; drop to the ground and change to pupa. After about from 7 to 60 days they emerge as flies. The injury done to the animals is inflicted by the worms or maggots. The debilitating efiect and the destruction of tissue kill the infested animals in a few days. The screw-worm destroys untold numbers of domestic and wild animals andthis losscosts livestock owners many millions of dollars annually. I g The stable fly (Stomoxys calcitraits), also'calledthe stock fly and'the bitingshousefiy,.is found inall'the-temperate regions of the world. The adults, both maleand female, are vicious bloodsuckers with long, piercing mouth parts that on penetrating the skin-cause considerable pain to animals or human beings: This fiy has been shown to be capable of carrying such livestock diseases as anthrax, swamp fever, and surra, as well as infantile paralysis of man. Althoughthe stablefly is prih'cipal-ly ananii" to and=animals; in large 'outbr'ealc s it frequeiitl ki s horses and cattle by c'ausingtlre'rn continuous worr and loss of blood: I The mille production of dairy h'erds' is loweredduring every stable fly season, the decrease flies are-abundant tliey'n'ra'y attack all parts'of thebodyi Unrnolested flies usually engorge to repletion inZ this minutes; sense-mmerstableniesmay beaciiiv afiy use of traps and sprays. Traps cannot be depended on for relatively short periods and therefore only those flies that happen to be on an animal will be caught. Sprays employing contact insecticides are effective only for several hours or at most a day or so, thus for good control frequent spraying is necessary. Furthermore, sprays employing contact insecticides are ineffective against parasites in all stages of growth. 7

The treatment of these and other parasites by presently employed methods are inadequate for obtaining good control. Some of the known materials have been of little efficacy, others impractical because of the frequency of treatment required, and still others have an adverse effect onthe metabolism of the treated animal; The need for simple and inexpensive methods for the control of parasite infection is well recognized as constituting one of the major problems in animal husbandry;

It is an objectof the present invention to provide a new class of chemical compounds. A further object is to provide an improved method for controlling parasites attacking warm-blooded animals. Another object is the proout at a temperature of from 3 to 45 C. with such rate of addition and cooling or heating as required to maintain the temperature in the desired range. The by-product in vision of a method wherein a systemic agent is employed I for the control of parasites attacking warm-blooded animals. Another object is to provide a new class of chemicalcompounds useful for systemic control of parasites. An additional object is the provision of novel compositions adapted to be employed in the new method for controlling parasites. from the following specification and claims.

The new phosphoramidates represented by the structure are colorless or light colored liquids or low-melting solids, soluble in many organic solvents and substantially insoluble in water. These compounds are useful for the systemic control of parasites attacking warm-blooded ani- I mals. In addition, they may be employed .as constituents of insecticidal and microbi cidal compositions as well as in herbicidal compositions.

v Various methods may be employed in the preparation ofnewphosphoramidates. One procedure consists of reacting a halophenyl phosphorodichloridate having the structure with a lower aliphatic alcohol, ROH, or alkali metal alkoxide derived from the lower aliphatic alcohol, ROM

wherein M represents an alkali metal, to form an intermediate halophenyl alkyl phosphorochloridate having the structure Other objects will become apparent the first step of the reaction is hydrogen chloride if free alcohol is employed or alkali metal chloride if the alkoxide is employed. When the by-product is hydrogen chloride, the latter is allowed "to exit from the reaction mixture as a gas. When the by-product is alkali metal chloride, it may be removed from the reaction mixture, if desired, by washing with water. The by-product in the second step is hydrogen chloride which may beremoved, preferably as a hydrochloride salt of the amine or ammonia. Following completion of the reaction, the phosphoramidate is separated by conventional means.

In a representative preparation by a preferred method employing aliphatic alcohol as reactant, 1 mole of lower aliphatic alcohol in an inert solvent such as methylene chloride is added portionwise with agitation to 1 mole of halophenyl phosphorodichloridate dispersed in the same solvent, and the mixture agitated for a time sufiicient to allow completion of the reaction with the formation of a halophenyl alkyl phosphorochloridate intermediate and hydrogen chloride lay-product. The hydrogen chloride by-product is removed from the reaction site by agitation and by bubbling an inert gas such as nitrogen through the mixture. The remaining mixture containing a halophenyl alkyl phosphorochloridate is cooled to about 15 C. and about 2 moles of ammonia or aliphatic amine added portionwise thereto with cooling and agitation The resulting mixture was allowed to warm to about 60 C. to complete the reaction with the formation of the desired halophenyl alkyl phosphorarnidate product and amine hydrochloride or ammonium chloride by-product. The .reaction mixture is then washed repeatedly with water to remove the amine hydrochloride or ammonium chloride by-product, and. dried with a; drying agent such as calcium sulfate or sodium sulfate. The solvent is removed from the resulting solution by vaporization to recover the phosphoramidate product as residue. The latter maybe purified by distillation'or recrystallization. 1

When alkali metal alkoxide is employed instead of agitated for a time suificient to allow completion of the reaction with the formation of halophenyl alkyl phosphorochloridate intermediate and alkali metal chloride by-product. The latter may be removed, if desired, from the'reaction mixtureby washing with water. The halo- 1 be reacted with ammonia or alkyl amine as previously excess of ammonia or lower aliphatic'amine. The reactron may be carried out in an inert organic solvent such as methylene chloride, chlorobenzene, chloroform, benzene, ether, and carbon tetrachloride. The reaction between the halophenyl phosphorodichloridate and lower aliphatic alcohol is carried out at a temperature of from about 10 C. to 110 C. The reaction between the halophenyl alkyl phosphoro'chloridate and lower aliphatic amine is carried described.

,Thehalophenyl phosphorodichloridate employed as starting material may be prepared by reacting 1 mole of an appropriate halophenol with about 4 moles phosphorus oxychloride in the temperature range of from about 30 to C. in the presence of a catalytic amount of magnesium chloride. Following the reaction the mixture is fractionally distilled under reduced pressure to obtain the desired halophenyl phosphorodichloridate In an alternative method for the preparation of the phosphoramidates of the present invention, an alkali metal derivative of the appropriate halophenol having the structure i r Oalkali metal a r-aces with an alkylphosphoramidic dichloride having the S'tilib'tfif (J/Cl RNHP to form an intermediate halophenyl alkylphosphoramidochloridate having the structure followed by the reaction of the latter with alkali metal alkoxi'de having the structure, RO-alkali metal, to produce the desired phosphoramidate compound previously defined. Good yields are obtained by employing substantially equim'olar proportions of each of the reactants. The first step of the reaction may be carried out by adding an alcohol solution of metal halophenoxide to a solu-v tion of the alkylphosphoramidic dichloride in a neutral solvent such as methylene chloride or chlorobenzene in the temperature range of from to 60 C. The reaction is exothermic and temperature control is maintained by the rate of addition of the reactants as well as by cooling. The second step of the reaction may be carried out by adding an alcohol solution of alkali metal alkoxide to a solution of halop'henyl' alkylphosphorarnidochloridate in an inert solvent in the temperature range of from 10 to 80 C. The byproduct in both steps of reaction is alkali metal chloride. The try-product alkali metal chloride may be removed from the reaction mixture, if desired, by washing with water. Following the completion of the reaction, the phosphoramidate product is separated by conventional means.

In'a representative preparation, 1 mole of alkali metal halophenoxide is added portionwise with stirring to 1 mole of alkylphosphoramidic dichloride, and the mixture agitated for a time suflicient to allow completion of the reaction with the formation of halophenyl alkylphosphoramidochloridate intermediate and alkali metal chloride by-product. The resulting mixture containing the intermediate phosphoramidochloridate is cooled and 1 mole of alkali metal alkoXide added thereto with cooling and agitation. The resulting mixture is warmed to about 50 C. to complete the reaction with the formation vof the desired halophenyl alkyl phosphoramidate product and sodium chloride by-product. The product is recovered from the reaction mixture by adding an inert water-immiscible solvent thereto, washing with dilute alkali and water to remove the alkali metal chloride by-product and acidic impurities, dried, and. vaporized to remove the solvent and recover the desired phosphoramidate product as residue. The latter may be further purified by distillation or recrystallization.

The alkylphosphoramidic dichloride employed as starting material may be prepared by reacting the hydrochloride of an appropriate alkylamine with a molar excess Ezc'dmple l.='-2 ;4,5-trichlorophenyl ethyl ethylphosphoramidare 4.6 grams (0.2 mole) of sodium was dissolved in 206 milliliters of absolute ethanol to produce sodium ethoxide. One-half of the resulting sodium ethoxide (0.1 mole) solution was intimately mixed with 19.8 grams (0.1 mole) of 2,4,5-trichlorophenol to form sodium 2,4,5-trichlorophenoxide. The resulting phenoxide solution was added with stirring and cooling to 16.2 grams (0.1 mole) of ethylphosphoramidic dichloride (boiling point, 139 143.5 C. at 22 millimeters; density of 1.36 at 23 C.)..v The temperature was maintained between 39 to 43 C. during the addition. After completion of the addition, stirring was continued for 5 minutes while the reaction mixture was allowed to warm to 50 C. to complete the reaction and form the intermediate 2,4,5-trichlorophenyl ethylphosphoramidochloridate. Thereafter the mixture was cooled at once to 29 C. and the remaining half of the sodium ethoxide (0.1 mole) solution above prepared added thereto portionwise with stirring while the temperature was maintained between 29 and 32 C. Thereafter, stirring was continued for 5 minutes while the mixture was allowed to warm to 41 C. to complete the reaction and to produce a 2,4,5-trichlorophenyl ethyl ethylphosphoramidate product. The alcohol solvent was vaporized from the reaction mixture containing the product and the product residue dissolved in carbon tetrachloride. The resulting solution waswashed successively with dilute alkali and water and then dried over anhydrous sodium sulfate. The carbon tetrachloride was then vaporized under reduced pressure to obtain the 2,4,5- trichlorophenyl ethyl ethylphosphoramidate product as a pale orange oil which slowly crystallized to a white solid. The product in the form of a supercooled liquid had a density of 1.33 at 23 C. Example 2.-2,4,5-trichlor0phenyl ethyl methylphosphoramidate A solution containing 0.17 mole of sodium ethoxide,

' prepared by adding 3.92 grams of sodium with milliliters of absolute ethanol, was added portionwise over a period of 16 minutes with stirring and cooling to a solution of 59.3 grams of 92.5 percent 2,4-5-trich1orophenyl phosphorodichloridate (density, 1.67 at 24 C.; 0.19

mole). The mixture was maintained in thetemperature range of from 12 to 22 C. during the addition. After completion of the. addition, the stirring was continued for a period of 5 minutes while the temperature was kept at 22 C. to'complete the reaction to produce the intermediate ethyl 2,4,5-trichloropheuyl phosphorochloridate product.

6.5 grams (0.21 mole) of methyl-amine was added over a 4 minute period to the remaining one-half of the reaction mixture above prepared and containing ethyl 2,4,5-trichlorophenyl phosphorochloridate. The mixture was maintained in the temperature range of 22 to 33 C. during the addition. After completion of the addition the mixture was stirred for an additional ten minutes to complete the reaction to obtain a 2,4,5-trichlorophenyl ethyl methylphosphoramidate product. The reaction .mixture containing the product was washed with dilute aqueous alkali and water, dried over sodium sulfate and distilled under reduced pressure to remove the solvent and lower volatile impurities and to recover a purified 2,4,5-trichloropheny1 ethyl methylphosphoramidate product as a yellow oil residue. The latter had a density of 1.33 at 24 C.

Example 3.2,4dichl0r0phenyl methyl methylphosphoramidate C. to a solution of 280 grams (1 mole) of 2,4-diob1orophenyl phosphorodichloridate in 1 liter of methylene chloride. After completion of the addition, the reaction mixture was maintained in the temperature range of from 20 to 30 C. for 22 hours to complete the reaction and to produce a 2,4-dichlorophenyl methyl phosphorochloridate intermediate product and hydrogen chloride byproduct. The hydrogen chloride by-product was removed from the reaction medium by mechanical agitation and by bubbling nitrogen gas through the reaction medium.

The resulting medium containing 1 mole of 2,4-dichlorophenyl methyl phosphorochloridate was cooled to 4 C. and a solution of 70 grams (2.2 moles) of methylamine in 70 milliliters of methylene chloride added thereto with stirring and cooling to maintain the reaction mixture below 15 C. After completion of the addition the reaction mixture was warmed to 28 C. and maintained at that temperature for 3 hours to complete the reaction to obtain a' 2,4-dichlorophenyl methyl methylphosphoramidate product and methylamine-hydrochloride by-product. The mixture was then extracted three times with approximately 500 milliliter portions of water to remove the methylamine-hydrochloride, and the organic solution then dried with anhydrouscalcium sulfate.

The organic solution was heated to distill off the solvent and to recover the product as a light yellow oil. The

. latter Was crystallized from petroleum ether, (boiling range of 30-60 C.) 'to obtain a purified 2,4-dichlorophenyl methyl methylphosphoramidate product as a white crystalline material melting at 54-55 C. The product had a chlorine content of 25.99 percent and a phosphorus content of 11.59 percent. The theoretical values are 26.25 percent and 11.48 percent respectively.

Exrzmple 4.-2,4-dichlorophenyl methyl normal-butylphosphoramidate A solution of 64 grams (2 moles), of methanol in 100 milliliters of methylene chloride was added portionwise.

win 150 milliliters of methylene chloride was added dropwise with stirring to a solution resulting from mixing 606 grams of the solution above prepared and containing 0.49

mole of 2,4-dichlorophenyl methyl phosphorochloridate with 50 milliliters of methylene chloride. The addition was carried out while maintaining the temperature below 11 C. over a period of about 45 minutes. After completion of the addition, the mixture was allowed to warm to a temperature of 26 C. to complete the reaction and to obtain a 2,4-dichlorophenyl methyl normal-butylphosphoramidate product and normal-butylamine-hydrochloride by-product. The reaction mixture was washed with water to remove the amine hydrochloride by-product, and then fractionally distilled to obtain a 2,4-dichlorophenyl methyl normal-butylphosphoramidate boiling from 151 to 155 C. at 0.1 to 0.2 millimeters pressure. The product has a chlorine content of 23.25 percent and a nitrogen content of 4.02 percent. The theoretical values are 22.70 percent and 4.48 percent respectively.

Example 5.-2-chl0rophenyl methyl isopropylphosphor- 16 grams (oiore of methanol in 50 milliliters of methylene chloride was added with stirring to a solution 123 grams (0.5 mole) of 2-chlorophenyl phosphorodichloridate in 400 milliliters of methylene chloride while the temperature was maintained below 26 C. After completion of the addition, agitation was continued and nitrogen gas bubbled through the reaction mixture for 3 hours to complete the reaction to produce Z-chlorophenyl methyl phosphorochloridate intermediate and to remove hydrogen chloride by-product. The mixture was heated to a temperature of 50 C. at 2 millimeters to remove the solvent and to recover the 2-chlorophenyl methyl phosphorochloridate intermediate product.

60 grams (0.25 mole) of 2-chlorophenyl methyl phosphorochloridate, prepared as above described, was dissolved in 250 milliliters of methylene chloride, cooled to a temperature below 15 C. and a solution of 30 grams (0.25 mole) of isopropylamine in 50 milliliters of methylene chloride added thereto with cooling and stirring. After completion of the addition the mixture was gradually warmed to 23 C. over a period of 3.5 hours to complete the reaction and to obtain 2-chlorophenyl methyl isopropylphosphoramidate product and isopropylamine-hydrochloride by-product. The reaction mixture was washed with water to remove isopropylamine-hydrochloride by-product, thereafter dried over anhydrous calcium sulfate and distilled to remove the solventand to recover the 2-chlorophenyl methyl isopropylphosphoramidate product as yellow liquid. The latter solidified on standing at room temperature for about 2 days. The solid was recrystallized from petroleum ether (boiling range 30-60 C.) to obtain a purified product as a white crystalline solid melting at 55.5 56 C.

Example 6.--3,4-dichlor0phenyl methyl isopropylphosphoramidate In a similar manner, a solution of 64 grams (2 moles) of methanol was reacted with 560 grams (2 moles) of 3,4-dichlorophenyl phosphorodichloridate to obtain 3,4- dichlorophenyl methyl phosphorodichloridate intermediate product.

A solution of 71 grams (1.2 moles) of isopropylamine in 200 milliliters of methylene chloride was added dropwise to 667 grams of a methylene chloride solution c011- taining 0.592 mole of 3,4-dichlorophenyl methyl phosphoro'chloridate above prepared while the mixture was agitated and maintained at a temperature below 15 C. Thereafter, the mixture was allowed to warm to 30 C. over a period of about 3 hours to complete the reaction, then washed with water followed by heating to remove the solvent and to recover the 3,4-dichlorophenyl methyl isopropylphosphoramidate as a liquid having a chlorine content of 23.95 precent and a nitrogen content of 4.74 percent. The theoretical values are 23.80 percent and 4.80 percent respectively. The molecular weight of 3,4- dichlorophenyl methylisopropylphosphoramidate is 298.

Example 7.-2-chtorophenyl methyl phosphoramidate In a similar manner, 64 grams (2 moles) of methanol in 320 milliliters of methylene chloride was added pertionwise with stirring to a cooled solution of 491 grams (2 moles) of 2-chloropl1enyl phosphorodichloridate in 1000 milliliters of methylene chloride. Thereafter, nitrogen gas was bubbled through the mixture for a period of 30 hours while the temperature was maintained between 23 and 30 C; to obtain 2213 grams of methylene chloride solution of 2- chlorophenyl methyl phosphorochloridate intermediate product.

18 grams (1.06 moles) of anhydrous ammonia dissolved in milliliters of methylene chloride was added with stirring to 553 grams of the solution above prepared and containing 0.5 mole of 2-chlorophenyl methyl phosgangsta Example 8.-2,4,5-trichlorphenyl methyl phosphoram-iclate In a similar manner, 128 grams (4 moles) of methanol in 200 milliliters. of methylene chloride was added with cooling and stirring to 1258 grams (4 moles) of 2,4,5-trichlorophenyl phosphorodichloridate in 1500 milliliters of methylene chloride, nitrogen gas bubbled through the resulting mixture to remove the hydrogen chloride byproduct and. to obtain 2,4,5-trichlorophenyl methyl phosphorochloridate product. The methylene chloride solution containing 4 moles of 2,4,5-trichlorophenyl methyl phosphorochloridate weighed 4000. grams.

A solution of 18 grams (1.05 moles) of anhydrous. ammonia in 150 milliliters of methylene chloride and maintained at a temperature of from 30' to -40 C. was added portionwise to 5 00 grams of the 2,4,5-trichlorophenylmethyl phosphorochloridate (containing 0.5 mole) solution above prepared diluted with 200 milliliters of methylene chloride. The addition was carried out at such a rate to maintain the temperature of the reaction mixture below C; The mixture was then allowed to warm to 30 C. to complete the reaction and to obtain 2,4,5atrichlorophenyl methyl phosphoramidate product and ammonium chloride by-productw hichprecipitated as a white solid in the reaction mixture. The mixture was filtered, the precipitate washed several times with Water to remove the ammonium chloride by-product andto re cover 2 ,4,5-trichlorophenyl methyl product as a white crystalline Example 9.2,4,5-trichloro 2 henyl methyl methylplwsphoramidate phosphorarnidate solid melting at A solution of 33 grams (1. 06rnole). of methyl-amine in 95 milliliters of. methylene chloride-was added dropwise with agitation to a mixture of 5 00- grams of a solution containing 0.5 mole of 2,4,5J-trichlorophenyl methyl phosphorochloridate perpared as described" in Example 8 and 200 milliliters of methlyene chloride. The reaction mixture was maintained below 15 C. during the addition. After completionoi the addition the mixture'was gradually Warmed to 30 C. over a period of about two hours to complete. the reaction to obtain a 2,4,5-trichlorophenyl methyl methylphosphoramidate product and methylamine hydrochloride by-product. During the reaction some of the by-product precipitated in the mixture as a white solid. The mixture was washed with water to remove the by-product, then distilled to remove the solvent and to recover the 2,4,5-trichlorophenyl methyl methylphosphoramidate product as a white solid residue. The latter was recrystallized from methanol to obtain a purified product melting at 98-99 CI Example .10. -2,4,5-trichlorophenyl methyl tertiarybutylphosphoramidate.

dropwise with agitation to-a mixture 437 grams of a solution containing 0.437 mole of" 2,4,5-trichlorophenyl methyl phosphorochloridate prepared as described in Example 8 and 250 milliliters of methylene chloride. The reaction mixture was maintained below 15 C. during the addition. After completion of the addition, the mixture was warmed to 30 C. and then allowed to stand overnight at room temperature. Thereafter it was washed with water, heated to remove the solvent and to obtain a 2,4,5-tr'ichlorophenyl methyl tertiary-butylphosphoramidate product as a solid. The latter on recrystallization from petroleum ether melted at 9192 C.

Example 11 In a similar manner, the following compounds were prepared.

2-chlorophenyl methyl methylphosphoramidate having a melting point of 49 -5 1 C.. bythe reaction of 2-chloro phenyl phosphorodichloridate with methanol to produce the intermediate 2-chlorophenyl methyl phosphorochloridate followed by the reaction of the latter with methylamine. l

2-chlorophenyl methyl ethylphosphoramidate having a molecular weight of 249.5 by the reaction of 2-chlorophenyl phosphorodichloridate with methanol to produce the intermediate Z-chlorophenyl methyl phosphorochloridate followed by the reaction of the latter with ethylamine.

3 .4-dichlorophenyl methyl methylphosphoramidate having a molecular weight of 270 by the reaction of 3,4-dichlorophenyl phosphorodichloridate with methanol to produce the intermediate 3,4-dichlorophenyl methyl phosphorochloridate followed by the reaction of the latter with me'thylamine.

2,4-dichlorophenyl methyl isopropylphosphoramidate boiling from 138 to C. at 0.5 millimeter pressure by the reaction of 2,4-dichlorophenyl phosphorodichloridate with methanol to produce phosphorochloridate followed by the reaction of the latter with isopropylamine.

4-chlorophenyl ethyl methylphosphoramidate boiling at 144-146 C. at 0.20.3 millimeter pressure by the reaction of 4-chlorophenyl phosphorodichloridate with ethanol to produce the intermediate 4-chlorophenyl ethyl phosphorochloridate followed by the reaction of the latter withmethylamine.

2,4,5-trichlorophenyl methyl ethylphosphoramidate melting at 67 -68 C. by the reaction of 2,4,5-trichlorophenyl phosphorodichloridate with methanol to produce the intermediate 2,4,5-trichlorophenyl methyl phosphorochloridate followed by the reaction of the latter with ethylamine.

2,4;5-trichlorophenyl methyl isopropylphosphoramidate melting at 8384 C. by the reaction of 2,4,5-trichlorophenyl 'phosphorodichloridate with methanol to produce the intermediate 2,4,5-trichlorophenyl methyl phosphorochloridate followed by the reaction of the latter with isopropylamine.

Example 12 251.4 grams (1 mole) of'2,4,6-trichlorophenyl phosphorodichloridateis dissolved in 500 milliliters of chloroform and the mixture heated to the boiling point and maintained under reflux. To the refluxing mixture is added dropwise 46 grams (1 mole) of ethanol over a period of about one hour. After completion of the addition, the mixture is maintained at reflux temperature for an additional hour to complete the reaction and to produce a'2,4,6-trichlorophenyl ethyl phosphorochloridate intermediate and hydrogen chloride by-product. The mixture is thencooled to room temperature and nitrogen gas passed therethrough to remove any remaining hydrogen chloride by-product.

The resulting mixture containing 2,4,6-trichlorophenyl ethyl phosphorochloridate is cooled to about 33 C. and 86 grams (2 moles) of ethylamine added dropwise thereto while the temperature is maintained below 15 C. After completion of the addition, the mixture is warmed to room temperature and maintained at that temperature for about 1 hour to complete the reaction and to obtain a 2,4,6*trichlorpheny1 ethyl ethyl-phosphoramidate product and ethylamine-hydrochloride by-product as a white precipitate. The resulting mixture is washed with water several times to remove the hydrochloride byproduct, heated to distill the solvent and to recover the phosphoramidate product as residue. 2,4,6-trichlorophenyl ethyl ethylphosphoramidate has a molecular weight of 332.6.

Example 13.2,3,4,6-tetrachlorophenyl ethyl methylphosphoramidate 285.9 grams (1 mole) of 2,3,4,6-tetrachlorophenyl phosphorodichloridate is dissolved in 500 milliliters of chloroform and the mixture heated to the boiling point and maintained under reflux. To the refluxing mixture is added dropwise 46 grams (1 mole) of ethanol over a period of about one hour. After completion of the addition, the mixture is maintained at reflux temperature for an additional hour to complete the reaction and to produce a 2,3,4,6-tetrachlorophenyl ethyl phosphorochloridate intermediate and hydrogen chloride by-prod-uct. The mixture is then cooled to room temperature and nitrogen gas passed therethrough to remove any remaining hydrogen chloride by-product.

The resulting mixture containing 2,3,4,6-tetrachlorophenyl ethyl phosphorochloridate is cooled to about 3 C. and 62 grams (2 moles) of methyl-amine added dropwise thereto while the temperature is maintained below C. After completion of the addition, the mixture is warmed to about 30 C. and maintained at that temperature for about 1 hour to complete the reaction and to obtain a 2,3,4-,6-tetrachlorophenyl ethyl methylphosphoramidate product and methyl-aminehydrochloride by-product as a white precipitate. The resulting mixture is washed with water several times to remove the hydrochloride byproduct, heated to distill the solvent and to recover the phosphoramidate product as residue. Z,3,4,6tetrachlo rophenyl ethyl methylphosphoramidate has a molecular weight of 353. Example 14 in a similar manner, pentachlorophenyl methyl methyl-phos'phoramidate having a molecular weight of 373.4 is prepared by the reaction of pentachlorophenyl phosphorodichlo-ridate with methanol to produce the intermediate pentachlorophenyl methyl phosphorochloridate followed by the reaction of the latter with methyl-amine.

The phosphoramidates of this invention are useful products for a variety of agricultural and industrial applications. They are, for example, useful as herbicides for the control of germination and growth of undesirable vegetation such as radish (Raphanus sativus)'and-cranerry bean (Phaseolus vulgaris cran.) plants. They are also useful for use asaquatic herbicides for the control of submersed and floating aquatic weeds such as Ana'charis sp., Cabomba carolz'niana, Lysimastrum nummularia, Salvinia' rotundifolia, and Ceratophyllum sp. In a representative operation of its use as an aquatic'herbicide, methyl 2,4,5-trichlorophenyl phosphoramidate was employed for the control of aquatic weed Lysimastrum nummularia. In such operation, substantially complete control was obtained when the aquatic weed was exposed for 2 hours to a tank containing 100 parts by weight of methyl 2,4,5-trichlorophenyl phosphoramidate per million parts of aqueous medium. Further, they are useful as parasiticides, for the control of insects, microorganisms, plant pathogens and animal parasites. In a representative use as a plant pathogen, substantially complete controls of wheat rust disease were obtained when wheat plants susceptible to wheat rust disease caused by rust fungus (Puccinia graminis-tritici) were'sprayed in separate operations with an aqueous dispersion containing 0.25 pound of 2,4-dichlorophenyl methyl ethylphosphoramidate, 2,4-dichlorophenyl methyl butylphosphoramidate, 2- chlorophenyl methyl ethylphosphoramidate, methyl 2,4,5-trichlorophenyl methylphosphoramidate, methyl 2,4,5-trichlorophenyl ethylphosphoramidate or 3,4-dichlorophenyl methyl methylphosphoramidate in gallons of spray mediurn and thereafter inoculated with the disease organism. As insecticides, these compounds are useful for control of insects in all stages of growth and both as contact and as systemic insecticides. Thus, the phosphoramidates of this invention give good control of Mexican bean beetle (Epilachna varivestis) and southern armyworm (Prodenia eridania) when plants such as cranberry bean plants are sprayed with compositionscontaining phosphoramidates and thereafter infested with the insects. The phosphoramidates also give good controls of bean aphids (Aphis fabae) and two spotted spider mites (T etrrmychus bimaculatus) when infested plants are sprayed therewith. They are further useful for the control of household pests such as house fly (Musca d0- mestzca) and cockroach (Americana periplaneta).

It has also been discovered that by employing the new phosphoramidates good control of parasites attacking warm-blooded animals may be obtained and the growth characteristics of the animal may be improved. Further, the new phosphoramidates are found to be readily assimilable by warm-blooded animals and to control parasites attacking flesh, viscera or vascular system of the animals. These phosphoramidates are effective for systemically controlling parasites attacking-warm-blooded animals, without adversely affecting the animals. Thus, these compounds are of low toxicity and furthermore, are effective at a concentration heretofore not thought pos sible. Moreover, these phosphoramidates are not bound or incorporated or otherwise retained by fat and other tissues of warm-blooded animals in the manner and extent that is the case with other phosphorus containing compounds. I

The practice of this invention may be accomplished by an oral administration of phosphoraniidate, by spraying the animal with a composition comprising the active compound to permit absorption thereof through the skin, or by injecting the animal with a suitable solution of the active compound. In the preferred method for carrying out this invention, the phosphoramidate compound is administered to the animal to be treated by intramuscular injection. This method of treatment permits rapid absorption of the unaltered form of the phosphoramidate and further has the advantage of being an effective means for treatment of range cattle and other grazing animals. Moreover, there is absence of sterile abscesses in their administration.

The phosphoramidates of this invention which are particularly valuable are those which have the structure NE a wherein R and R is a lower alkyl radical containing from-l to 4 carbon atoms, each X is chlorine or hydrogen, and wherein at least one X is chlorine.

In carrying out this invention a therapeutic dose or dose sufficient to control pathogenic parasites without serious toxic eflects on warm-blooded animals is administered to the animal. The exact dose is dependent on the parasite to be controlled and the particular phosphoramidate compound employed, as well as upon whether the administration is to be made in a single dose or in multiple doses over a period of several days. Where a single dose is employed for the control of helminths good results are obtained when the phosphoramidates are administered'at a dosage of-SO to milligrams per kilogram of body weight of the animal. For the control of flies, fleas, lice and ticks, good results are obtained ass-4,937

. 1:5 when the phosphoramidates are employed at dosages as low as 20 milligrams per kilogram of body weight, while for the control ofs'crewworms and cattle grubs the phosphoramidat'cs give goodcontrols atdosages of 2.5 milligrams per kilogram or more of bodyweightf If desired, the compo unds may be administere'd'in "multiple doses over a period of several days. In such operations, it is preferred to employ a daily dosage of from 0.5 to 15 milligrams per kilogram of body weight.

The process of this invention may be carried out by intramuscular injection of asolution of the phosphoramidate compound in a suitable medium. By suitable medium is meant an inert liquid carrier which will not bring about degradation of the phosphoramidate compound and further will not irritate or adversely affect the animal to be treated. Suitable liquid carriers include diethyl succinate, ethyl acetate, propylene glycol, ethyl lactate, diethyl adipate, peanut oil and sesame oil.

V The systematic control by the novel compounds may also be achieved by administering the phosphoramidate to the animals orally in the unmodified form such as in gelatin capsules or pellets, or in admixture with an inriocuous adjuvant such as ethanol water, skimmed milk, syrups, edible oils, or other edible carriers; surface active dispersing agents, edible powders, commercial animal feeds, concentrates and vitamin and mineral supplements. The compounds may also be administered as a spray, preferably in a non-hydrolyzing medium such as in isoparaffin oil. The latter, boiling in the range of kerosene is characterized by low odor, low phytotoxicity and lower toxicity to animals than ordinary hydrocarbon oils of the same boiling range and contain no more than traces of olefins, napthenes o r aromatics and low percentage of normal paraflins, Otherliquid medium normally employed for animal sprays such as kerosene and diesel fuel, as well as aqueous spray'compositions wherein the phosphoramidate is dispersed With a suitable emulsify ing or dispersing agent may also be employed.

The exact concentration of thephosphoramidate compounds to be employed in thecompositions may vary provided that a 'sufiicient amount be administered to provide the required dosage of the active agent. For ex ample, where'direct administration by intramuscular injection is to 'be employed, itis" generally desirable that the injectible' solution contain a fairly high concentration of the active agent. A liquid composition containing from about 35 to 55 percent of the agent is considered most practicable. Where direct oral administration to Although the methods and compositions of the present invention and the phosphorus compounds therein employed are useful for the control of a number of parasites in warm-blooded animals, such teaching is not to be cons trued that the methods, compositions and compounds are equivalents for the control of a particular parasite or the life stage of such parasite, or for the control of such parasite or life stage thereof in a particular animal.

Since many of the parasites are seasonal in their appearance, the present invention is advantageously practiced with certain'parasites at a particular time of the year. Thus with cattle grubs, Hypotierma lineatum and how's, it is preferred that the administration for their control he carried out in the fall and quite soon after the disappearance of the heel and bomb flies. The disappearance of these flies varies somewhat depending upon the climate. For the control of the cattle grub, Dermatobzfa. hominis, in the Central and. South American countries, it is desirable that the administration be carried out about four times each year. When following such practices good controls of cattle grubs are obtained with a minimum of damage to the animal from the migration of Lhe grub. Further, the grubs are controlled before they have a chance to adversely affect the animal or its rate of growth, or reduce the "value of the animals hide.

The control of animal parasites attacking Warmblooded animals by the administration of phosphoramidates is illustrated by the following examples:

Example 15 The phosphorarnidate. compounds represented by the structure,

(Bl/OOH;

. for the control of cattlegrub is' yearling calvesinfe'sted an animal is to be employed, liquid or solid compositions containing from 4 to 95 percent by weight of the phosphoramidate may be used to supply the desired, dosage. Where the compounds are provided, as a constituent of the principal food ration, satisfactory results are obtained with food rations containing a minor but efiective am ount of the phosphoramidate compounds. The exact amount of the compound to be incorporated. in the, ration isfdependent upon the food consumption and feeding habits of the animals concerned. In animals such as pigs and mice, the required dosage may be supplied with feed compositions containing from 0.01 to 1 percent by weight of active agent. In fowl, the required dosage may be supplied with mash compositions containing from 0.01 to 0.25 percent by weightof the systemic agents. Where the compound is provided as a constituent of feedsupplements, good results are obtained with supplements con-.

therewith. In such operations, each phosphoramidate compound is administered by intramuscular injection. The injectible solution is administered by injection in the hip of'the animalin an amount suflicient to supply a dosage of. 10 milligrams per kilogram of body weight. A group of simila'rlyinfested yearling calves is left untreated to serve as checks;

The inj'ectible solution wasprepared by dissolving the phosphoramidate compound. in diethyl succinate to provides. concentration of 500 milligrams of the phosphoramidate per milliliter of solution.

At intervals of four and eight weeks following treatment the calves are examined and weighed. The examination shows that the treatments have no adverse effect on the animal or on the growth rate.

20 weeks following treatment the animals are examined for evidenceof nodular dermal cysts caused by cattle grub larvae. Cattle treated with phosphoramidate compounds are found to harbor 2 or less grub larvae while untreated calves harbor an average of 10 live larvae per animal. Y

' Example 16 A 119 kilogram calf heavily infested in an area of a neck wound with screwworm was injected in the hip with 1.19 milliliters of a diethyl succinate solution of 2,4dichlorophenyl methyl methylphosphoramidate prepared as described in Example 15.

The dosage is suflicient tosupply 5 milligrams of 2,4- dichlorophenyl methyl methylpliosphoramidate per kilogram of body weight. Three hours following the administration, the wounds were examined and found to be substantially free oflive screwworm. Twenty-four hours following administration, the wounds were found to be completely free of live screwworms.

Example 17.

Example 18 2,4-dichlorophenyl methyl methylphosphoramidate was employed as a systemic agent for the control of stable flies feeding on the skin surfaces of cattle. The composition employed and the dosing operation was as previously described with the phosphoramidate compound being administered to a 119 kilogram calf at a dosage of milligrams per kilogram of body weight.

Two hours after injection, stable flies were allowed methylphosphoramidate, chlorophenyl methyl isopro- 'pylphosphoramidate, 2,4,5-trichlorophenyl methyl isopropylphos'phorarnidate and '2-chlorophenyl methyl phosto feed on the skin of the animalfor a period of 15 minutes and thereafter caged and observed for 24 hours for mortality. As a result of the treatment, a 100 percent kill of stable flies feeding on the calf dosed with 2,4-dichlorophe'nyl methyl methylphosphoramidate was obtained. No adverse effect on the calf attributable to the phosphoramidate compound was observed following the treatment.

Example 19 with 3,4-dichlorophenyl methyl 1 methylphosphoramidate showed 100 percent mortality of the flies. I

' Examplc 20 Ina field test conducted in late fall soon after the heel and hot flies deposited eggs, l7 calves having an average vation of the flies which had fed on thecalf treated weight of 35f) pounds were taken'for systemicgrub control treatment. 7 No grubs were visible on the backs of the calves at this time. Two of the calves were injected with a diethyl succinate solution of 3,4-dichlorophenyl methyl methylphosphoramidate prepared as described in A sheep weighing 23 kilograms and voiding an average of about 5000 ova of gastro-intestinal nematodes per gram of feces is treated with unmodified 2,4,5-trichlorophenyl methyl methylphosphoramidate in the form of a gelatin capsule. The ova includes those of Bunostomum sp., Haemonchus sp., Oesophagostomum sp., Ostertagi sp., Trichostrongulus sp., and Cooperia sp. The amount administered corresponds to 156 milligrams per kilogram of' body weight. Following the treatment, the sheep voids large numbers of nematodes. One week following treatment the feces are examined and found to be substantially free of nematode ova.

Example 22 Various phosphoramidates, 2,4,5-trichlorophenyl ethyl pho'ramidate are employed as systemic agents for the control'of stable flies feeding onthe skin of mice. ln-such operations, the various phosphoramidates are directly introduced intothe stomach of the mouse at a dosage of 200 milligrams per kilogram of body weight. One hour following the introduction, the mice are restrained and 10 to 15 stable flies allowed to feed on the animal for a period of one hour. The stable flies are thereafter observed for 24 hours for mortality. It is found that at the dosage of 200 milligrams per kilogram the mortality of the stable fly is over percent. Stable flies fed on untreated check mice show no mortality after 24 hours. i

7 Example 23 Six head of cattle infested with hot larvae (Dermatobz'a hominis) are injected in the hip with an injectible ethyl acetate solution of 2,4-dichlorophenyl methyl methylphosphoramidate prepared in a manner similar to that described in Example'lS at a dose of 10 milligrams per kilogram' On the third day following treatment, the efficacy of'the treatment is determined by extracting all bots from the cyst and determining the percentage that have been killed. It is found that in all of the cattle thus treated substantially complete kill is obtained. Examination of the cattle five weeks after treatment shows no reinfestation with bots. During this period, no toxicity or injurious effect to the cattle is seen.

Exarriple 24 An injectible solution of 2,4,5-trichlorophenyl ethyl methylphosphoramidate prepared as described in Examplel5 is injected in the hip ofa cow having a heavy infestation ofshort nosed cattle louse, Haematopenus euryster nug At the time of injection, thousands of lice are found 'on the-cow, and the-skin along the side of the neck and brisket aredenuded of hair by the parasite. The amount. administered is suflicient to supply milligrams of 3,4,6-trichlorophenyl ethyl methylphosphoramidate per kilogram of body weight of'the cow. Examination ofthe'skin surfaces of the cow at the end of 48 hours and 72 hours following treatment show 100 percent kill of the short nosed cattle louse. No adverse effect upon the cow attributable to the phosphorarnidate compound is observed following treatment.

Example 25 Concentrate compositions are prepared containing at least one of the following phosphoramidates as active toxicant: 2,4-dichlorophenyl methyl methylphosphoramidate, 3,4-dichlorophenyl methyl methylphosphoramidate, 2,4,5-trichlorophenyl methyl methylphosphoramidate, 3,4-chlorophenyl isopropyl methylphosphoramidate and 2,4-chlorophenyl methyl isopropylphosphoramidate. The concentrate compositions are wettable powders containing'25 parts by weight of phosphoramidate compound, 44 parts of kaolin clay, 28 parts of diatomaceous earth, 2 parts of a polymerized sodium salt of a substituted benzoid alkyl sulfonic acid (Daxad Number 27) and 1 part of sodium naphthalene sulfonate (Nekal A). These 'ingestible concentrate compositions are prepared by mechanically mixing and grinding together the indicated constituents.

20 grams of theconcentrate composition containing 5 grams of 2,4-dichlorophenyl methyl methylphosphoramidate prepared as above described is dispersed in milliliters of water to obtain an aqueous drench. The

aqueous drench is orally administered to. yearling calves infested with cattle grub larvae. The composition is found to have been controls of the cattle grub larvae in the treated calves.

17 Example 26 an amount sufiicient to supply 25 milligrams of phosphoramidate compound per kilogram of body weight.

. Following treatment examination of the feces shows substantially complete reduction in number of nematode ova.

Example 27 amounts suflicient to supply dosages of 130 milligrams of phosphoramidate compound per kilogram of body weight. A similar flock is fed unmodified mash to serve as checks. Such treatment controls blood-sucking parasites of fowls such as fleas (Ceratophyllus gallinae), fowl ticks (Argas pericus) and mites (Dermanyssus gallinae).

Example 28 Concentrate compositions prepared as described in Example 25 are dispersed in water to produce a spray composition containing 0.75 part by weight of the phosphoramidate compound. These compositions are adapted to be employed to supply a chemotherapeutic dose of a phosphoramidate compound. When so employed these compositions give good control of many parasites attacking animals.

We claim: 1. A phosphoramidate represented by the structure t on 01., NHR

wherein R represents a lower alkyl radical containing 7 from 1 to 4 carbon atoms, inclusive, R is selected from the group consisting of hydrogen and a lower alkyl radical containing from 1 to 4 carbon atoms, inclusive, and n represents an integer of from 1 to 5, inclusive.

2. 2,4-dichlorophenyl methyl methylphosphoramidate. 3. 3,4-dichlorophenyl methyl methylphosphoram-idate. 4. 4-chloropheny1 methyl methylphosphoramidate.

5. 2,4,5-trichlorophenyl methyl methylphosphoramidate.

6. 2-chlorophenyl methyl phosphoramidate.

7. A method for controlling parasites attacking warmblooded animals which comprises administering to the animal a chemotherapeutic dosage of a systemic agent comprising a phosphoramidate having the formula C1D 0 OR wherein R represents a lower'alkyl radical containing from 1 to 4 carbon atoms, inclusive, R represents a member of the group consisting of hydrogen and a lower alkyl radical containing from 1 to 4 carbon atoms, inelusive, and n represents an integer of from 1 to 5, inclusive.

8. In the practice of animal husbandry, the step of administering to a warm-blooded animal a systemic agent in an amount sufiicient to provide from 0.5 to milligrams of the systemic agent per kilogram of body weight of the animal, said systemic agent being a phosphoramidate having the formula C111 0 OR wherein R represents a lower alkyl radical containing from 1 to 4 carbon atoms, inclusive, R represents a member of the group consisting of hydrogen and a lower alkyl radical containing from 1 to 4 carbon atoms, inclusive, and n represents an integer of from 1 to 5, inclusive.

9. A composition comprising a systemic agent, said systemic agent being a phosphoramidate having the formula Cln 0 OR wherein R represents a lower alkyl radical containing from 1 to 4 carbon atoms, inclusive, R represents a member of the group consisting of hydrogen and a lower alkyl radical containing from 1 to 4 carbon atoms, inclusive and n represents an integer of from 1 to 5, inclusive, and in intimate admixture therewith, an innocuous adjuvant.

References Cited in the file of this patent UNITED STATES PATENTS 2,552,541 Drake et a1. May 15, 1951 2,552,574 Moyle et al. May 15, 1951 2,852,469 Hugel et a1. Sept. 16, 1958 2,855,422 Kauer et a1. Oct. 7, 1958 

8. IN THE PRACTICE OF ANIMAL HUSBANDRY, THE STEP OF ADMINISTERING TO A WARM-BLOODED ANIMAL A SYSTEMIC AGENT IN AN AMOUNT SUFFICIENT TO PROVIDE FROM 0.5 TO 150 MILLIGRAMS OF THE SYSTEMIC AGENT PER KILOGRAM OF BODY WEIGHT OF THE ANIMAL, SAID SYSTEMIC AGENT BEING A PHOSPHORAMIDATE HAVING THE FORMULA 